The authors’ observations
Treatment strategies for sleep disorders in patients with schizophrenia mainly target behavioral aspects of sleep, such as sleep onset and total sleep time, and rarely correct polysomnographic disturbances. Commonly used medications include atypical antipsychotics, benzodiazepines, zolpidem, zopiclone, and antidepressants with sedative properties (Table 1).1 However, new insights on sleep architecture patterns in these individuals have directed focus on other medications. Although antipsychotics, GABAA modulators, and melatonin provide some sleep benefits, none of these agents fully address characteristic sleep disturbances found in patients with schizophrenia.
Recent research has looked at GABAB modulators because of their unique function. GABAB receptors are located on pre-synaptic dopaminergic terminals and inhibit dopamine release and modulate glutamatergic regulation of dopamine. In the glutamate hypofunction model of psychosis, a GABAB agonist would cause disinhibition of glutamate modulation of mesolimbic dopamine and reversal of GABA transmission in the ventral tegmental area.9 Baclofen and γ-hydroxybutyric acid (GHB) currently are the only FDA-approved GABAB receptor agonists. Overall, trials of baclofen have not shown benefit for sleep disturbances in patients with schizophrenia,10,11 perhaps because of the drug’s poor liposolubility and consequent inability to cross the blood-brain barrier. Although hydrophilic like baclofen, GHB, which is also known as sodium oxybate and is FDA-approved for cataplexy due to narcolepsy, might have an advantage because of carrier-mediated transfer across the blood-brain barrier. GHB is thought to act directly as a neurotransmitter but also interacts with dopamine via the GHB receptor and with the GABAB receptor after it is converted to extracellular GABA.
Table 1
Schizophrenia and sleep dysfunction: The effect of psychotropics
| Medication/class | Comments |
|---|---|
| Atypical antipsychotics | In the CATIE study, a large proportion of patients had sleep problems despite antipsychotic treatment Atypicals may improve sleep acutely, but do not normalize it The long-term effects of atypicals on sleep architecture in schizophrenia are unclear; some studies show improved slow-wave sleep but in others slow-wave sleep is reduced |
| GABAA modulators (benzodiazepines, zolpidem, zopiclone) | Decrease sleep latency and nocturnal awakening Do not increase slow-wave sleep and overall sleep quality Decrease slow-wave sleep and REM sleep in rats May impair sleep architecture and cognition |
| Melatonin and modafinil | Melatonin may be useful for improving subjective sleep in patients with schizophrenia, although it does not improve slow-wave sleep parameters Modafinil may enhance cognition |
| GABAB receptor agonists | Few trials in humans but animal studies support a potential therapeutic role Minimal impact on REM sleep Increase slow-wave sleep Human studies with the GABAB agonist GHB show improvement in sleep architecture and subjective sleep |
| CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness; GHB: γ-hydroxybutyric acid; REM: rapid eye movement | |
| Source:Reference 1 | |
OUTCOME: A trip cut short
Mr. F does not return to the clinic as scheduled, but 2 months later the U.S. consulate of a Western European country contacts us because Mr. F had a bottle of oxcarbazepine with our contact information. After Mr. F returns to the United States, he tells us his story.
After his last outpatient visit, Mr. F relapsed on alcohol, became despondent over his weakness, and searched for a way to escape his alcohol cravings. He came up with a plan to relocate to an Islamic Middle Eastern country where alcohol is banned and its use heavily punished. Mr. F bought a one-way airplane ticket through a Western Europe connection and departed 7 days later without notifying his family or psychiatrist.
Mr. F’s flight to Western Europe was uneventful. After landing for a connecting flight, his mood improved, his outlook became hopeful, and his auditory hallucinations changed from derogatory to supportive. However, Mr. F became despondent after being barred from his next flight because he did not have a return ticket. He was stranded in the airport with little money and no extra clothing, only his passport and laptop. He slept in the airport and after 3 days set off into the city. Mr. F navigated subway stations, ate at soup kitchens, and sought shelter in hotel lobbies and churches. One week after Mr. F left the airport, the police detained him for disorganized behavior and refusing to vacate a church. He was transported to a hospital, admitted to the psychiatric unit for catatonia, and stabilized on olanzapine, 20 mg/d.
After 1 week, Mr. F was returned to the United States and hospitalized for further evaluation and treatment. On his first day back, Mr. F’s disorganized process appeared to improve. He was euthymic and reported good sleep, tolerable anxiety, and infrequent derogatory auditory hallucinations that were low in volume. On day 3, Mr. F’s mood deteriorated moderately. He became depressed and again experienced derogatory auditory hallucinations. He was internally preoccupied and showed reduced affect and psychomotor activity. Mr. F was discharged the next day to a state-run respite program with a structured plan for psychiatric follow-up, social services, and sobriety maintenance. He remained on olanzapine, 20 mg/d, because we anticipated he would need an adjustment period after his uncommon journey.